Erythropoietin is required for the development and maturation of red blood cells. This regulator of erythropoiesis acts by binding to its surface receptor on erythroid progenitor cells to stimulate proliferation and activation of the erythroid program and globin gene expression. Combinations of erythropoietin with inducers of fetal hemoglobin have been considered as potential therapy for adult hemoglobin disorders. Modification of erythropoietin receptor is a strategy to manipulate erythropoietin response. GATA-1 and SP1 binding sites in the proximal promoter are required for high level of erythropoietin receptor expression. We use cell transfection experiments in K562 erythroleukemia cells to show that while erythropoietin stimulation of erythroid progenitors increases production of the erythroid transcription factor GATA-1, GATA-1 in turn can further transactivate erythropoietin receptor. A direct consequence of GATA-1 induction is the decrease in expression of transcription factor GATA-2. Cell studies including primary human erythroid progenitor cultures and transfection of GATA-2 show that GATA-2 is important in deciding the fate between the megakaryocytic and erythroid lineages. These results were confirmed by flow analyses using antibodies to cell surface markers. The erythropoietin receptor is also expressed in cells of endothelial and neural origin as we observe in cultures of primary cells and continuous cell lines, and is particularly high in the embryonic brain determined by quantitative RT- PCR analyses of normal and human erythropoietin receptor transgenic mice. Reporter gene assays show that the promoter can drive expression in the neural tube as early as embryonic day 9.5. Erythropoietin receptor transcripts isolated from a human brain library suggest that in the adult, low level of brain expression is maintained in part by alternate transcriptional and post-transcriptional processing compared with hematopoietic tissue. As with hematopoietic tissue, brain expression can also be induced by anemic stress. Erythropoietin treatment induces proliferation of primary endothelial and muscle progenitors (myoblast or primary satellite cells). These results suggest that stimulation of progenitor cells by erythropoietin is not restricted to the erythroid lineage and that erythropoietin may play a more general role during development or stress. On going studies focus on the mechanism by which erythropoietin binding to its receptor stimulates hematopoietic and non-hematopietic cells and its role in development and stress response. - erythropoietin, receptor, expression, erythroid, hematopoietic, embryonic, brain, transgenic mouse